Steven R. Messé

Practice parameter: recurrent stroke with patent foramen ovale and atrial septal aneurysm: report of the Quality Standards Subcommittee of the American Academy of Neurology.

Objectives: 1) To evaluate the risk of subsequent stroke or death in patients with a cryptogenic stroke and a patent foramen ovale (PFO), atrial septal aneurysm (ASA), or both. 2) To establish the optimal method of stroke prevention in this population of patients. Methods: MEDLINE, the Cochrane database of systematic reviews, key meeting abstracts from 1997 to 2002, and relevant reference lists were searched to select studies that prospectively collected outcome data in cryptogenic stroke patients with and without interatrial septal abnormalities. Studies were also selected that prospectively compared at least two treatment options. The quality of each study was graded (class I to IV) using a standard classification-of-evidence scheme for each question. Risk analyses were performed and data were pooled when appropriate. Results: The literature search generated 129 articles of which only four fulfilled the inclusion and exclusion criteria. Two studies were graded class I, one study was graded class II, and one study was graded class IV for prognosis. Pooled results of the two class I and one class II studies demonstrated no increased risk of subsequent stroke or death in patients with PFO compared to those without (RR = 0.95, 95% CI 0.62 to 1.44). One class I study found increased risk of recurrent stroke in patients with PFO and ASA (annual rate = 3.8% versus 1.05%, RR = 2.98, 95% CI 1.17 to 7.58) but not increased risk of a composite of stroke and death (annual rate = 3.8% versus 1.8%, RR = 2.10, 95% CI 0.86 to 5.06). Regarding therapy, one study was graded class II, one study class III, and two studies class IV. Among patients with cryptogenic stroke and PFO or ASA, there was no significant difference in stroke or death rate in warfarin-treated patients relative to aspirin-treated patients and the confidence intervals were unable to rule out a benefit of one drug over the other (annual rate = 4.7% versus 8.9%, RR = 0.53, 95% CI 0.18 to 1.58). Minor bleeding rates were higher in the cohort of patients who received warfarin (22.9/100 patient-years versus 8.66/100 patient-years, rate ratio = 2.64, p < 0.001). No studies compared medical therapy with surgical or endovascular closure. Conclusion: PFO is not associated with increased risk of subsequent stroke or death among medically treated patients with cryptogenic stroke. However, both PFO and ASA possibly increase the risk of subsequent stroke (but not death) in medically treated patients younger than 55 years. In patients with a cryptogenic stroke and an atrial septal abnormality the evidence is insufficient to determine if warfarin or aspirin is superior in preventing recurrent stroke or death, but minor bleeding is more frequent with warfarin. There is insufficient evidence to evaluate the efficacy of surgical or endovascular closure.Objectives1) To evaluate the risk of subsequent stroke or death in patients with a cryptogenic stroke and a patent foramen ovale (PFO), atrial septal aneurysm (ASA), or both. 2) To establish the optimal method of stroke prevention in this population of patients. MethodsMEDLINE, the Cochrane database of systematic reviews, key meeting abstracts from 1997 to 2002, and relevant reference lists were searched to select studies that prospectively collected outcome data in cryptogenic stroke patients with and without interatrial septal abnormalities. Studies were also selected that prospectively compared at least two treatment options. The quality of each study was graded (class I to IV) using a standard classification-of-evidence scheme for each question. Risk analyses were performed and data were pooled when appropriate. ResultsThe literature search generated 129 articles of which only four fulfilled the inclusion and exclusion criteria. Two studies were graded class I, one study was graded class II, and one study was graded class IV for prognosis. Pooled results of the two class I and one class II studies demonstrated no increased risk of subsequent stroke or death in patients with PFO compared to those without (RR = 0.95, 95% CI 0.62 to 1.44). One class I study found increased risk of recurrent stroke in patients with PFO and ASA (annual rate = 3.8% versus 1.05%, RR = 2.98, 95% CI 1.17 to 7.58) but not increased risk of a composite of stroke and death (annual rate = 3.8% versus 1.8%, RR = 2.10, 95% CI 0.86 to 5.06). Regarding therapy, one study was graded class II, one study class III, and two studies class IV. Among patients with cryptogenic stroke and PFO or ASA, there was no significant difference in stroke or death rate in warfarin-treated patients relative to aspirin-treated patients and the confidence intervals were unable to rule out a benefit of one drug over the other (annual rate = 4.7% versus 8.9%, RR = 0.53, 95% CI 0.18 to 1.58). Minor bleeding rates were higher in the cohort of patients who received warfarin (22.9/100 patient-years versus 8.66/100 patient-years, rate ratio = 2.64, p < 0.001). No studies compared medical therapy with surgical or endovascular closure. ConclusionPFO is not associated with increased risk of subsequent stroke or death among medically treated patients with cryptogenic stroke. However, both PFO and ASA possibly increase the risk of subsequent stroke (but not death) in medically treated patients younger than 55 years. In patients with a cryptogenic stroke and an atrial septal abnormality the evidence is insufficient to determine if warfarin or aspirin is superior in preventing recurrent stroke or death, but minor bleeding is more frequent with warfarin. There is insufficient evidence to evaluate the efficacy of surgical or endovascular closure.

Hematoma Growth in Oral Anticoagulant Related Intracerebral Hemorrhage

Background and Purpose— Limited data suggest that intracerebral hemorrhage related to oral anticoagulant therapy (OAT ICH) is associated with more hemorrhage expansion and a worse prognosis than spontaneous ICH (SICH). Methods— We examined patients enrolled in the placebo arm of the CHANT study, a prospective randomized trial of a putative neuroprotectant in patients with ICH. All patients had neuroimaging within 6 hours of symptom onset and at 72 hours. Initial ICH volume and hemorrhage expansion were determined by a central reader. Multivariable logistic regression was used to determine factors associated with ICH expansion and mortality at 90 days. Results— Of 303 patients included, 21 (6.9%) had OAT ICH. Baseline median ICH volume was greater in patients with OAT ICH compared to SICH (30.6 versus 14.4 mL, P=0.03). Hemorrhage expansion (defined as >33% increase in ICH volume) occurred in 56% of patients with OAT ICH compared to 26% of SICH (P=0.006). Mortality was substantially higher in OAT ICH (62% versus 17%, P<0.001). In multivariable analysis, time to neuroimaging and oral anticoagulant use were independently associated with hemorrhage expansion, and age, gender, and oral anticoagulant use were independently associated with mortality. Conclusions— These findings confirm that OAT ICH is associated with more hemorrhage expansion and greater mortality than SICH.

Temporal Trends in Patient Characteristics and Treatment With Intravenous Thrombolysis Among Acute Ischemic Stroke Patients at Get With the Guidelines–Stroke Hospitals

BACKGROUND Substantial efforts over the past decade have increased rates of intravenous tissue plasminogen activator (tPA) use in the United States. We sought to determine changes in patient characteristics and rates of tPA use over time among hospitalized acute ischemic stroke (AIS) patients. METHODS AND RESULTS We analyzed all AIS patients (n=1 093 895) and those arriving ≤ 2 hours and treated with tPA ≤ 3 hours after onset (n=50 798) from 2003 to 2011 in the American Heart Associations Get with the Guideline-Stroke (GWTG-Stroke). Categorical data were analyzed by Pearson χ(2) and continuous data by Wilcoxon test. Intravenous tPA use ≤ 3 hours after onset increased from 4.0% to 7.0% in all AIS admissions and 42.6% to 77.0% in AIS patients arriving ≤ 2 hours and fully eligible for tPA (P<0.001). In univariate analysis, tPA use increased over time, especially in those aged >85 years, nonwhite, and with milder strokes (National Institutes of Health Stroke Scale 0-4). Door-to-image time (median 24 versus 20 minutes) and door-to-tPA time (median 81 versus 72 minutes) also improved, with ≈65% of tPA-treated patients getting brain imaging ≤ 25 minutes after arrival. Multivariable analysis showed that with each additional calendar year, the odds that an eligible patient would receive tPA increased by 1.37-fold, adjusting for other covariates. CONCLUSIONS The frequency of IV tPA use among all AIS patients, regardless of contraindications, nearly doubled from 2003 to 2011. Treatment with tPA has expanded to include more patients with mild deficits, nonwhite race/ethnicity, and oldest old age.

Percutaneous Device Closure of Patent Foramen Ovale for Secondary Stroke Prevention

The optimal therapy for prevention of recurrent stroke or transient ischemic attack in patients with cryptogenic stroke and patent foramen ovale has not been defined. Although numerous observational studies have suggested a strong association between patent foramen ovale and cryptogenic stroke, a causal relationship has not been convincingly established for the majority of affected patients. Treatment choices include medical therapy with antiplatelet agents or vitamin K antagonists, percutaneous device closure, or open surgical repair. Whereas suture closure of an incidental patent foramen ovale is performed routinely during the course of an operation undertaken for another indication, primary surgical repair is rarely advocated in the current era. The choice between medical therapy and percutaneous device closure has been the subject of intense debate over the past several years, albeit one that has not been adequately informed by randomized, prospective clinical trial data to permit an objective comparison of the relative safety and efficacy of these respective approaches. Enrollment in clinical trials has lagged considerably despite frequent calls for participation from the US Food and Drug Administration and major professional societies. Completion and peer review of ongoing trials are critical steps to establish an evidence base from which clinicians can make informed decisions regarding the best therapy for individual patients. The present advisory strongly encourages all clinicians involved in the care of appropriate patients with cryptogenic stroke and patent foramen ovale--cardiologists, neurologists, internists, radiologists, and surgeons--to consider referral for enrollment in these landmark trials to expedite their completion and help resolve the uncertainty regarding optimal care for this condition.

Stroke After Aortic Valve Surgery Results From a Prospective Cohort

Background— The incidence and impact of clinical stroke and silent radiographic cerebral infarction complicating open surgical aortic valve replacement (AVR) are poorly characterized. Methods and Results— We performed a prospective cohort study of subjects ≥65 years of age who were undergoing AVR for calcific aortic stenosis. Subjects were evaluated by neurologists preoperatively and postoperatively and underwent postoperative magnetic resonance imaging. Over a 4-year period, 196 subjects were enrolled at 2 sites (mean age, 75.8±6.2 years; 36% women; 6% nonwhite). Clinical strokes were detected in 17%, transient ischemic attack in 2%, and in-hospital mortality was 5%. The frequency of stroke in the Society for Thoracic Surgery database in this cohort was 7%. Most strokes were mild; the median National Institutes of Health Stroke Scale was 3 (interquartile range, 1–9). Clinical stroke was associated with increased length of stay (median, 12 versus 10 days; P=0.02). Moderate or severe stroke (National Institutes of Health Stroke Scale ≥10) occurred in 8 (4%) and was strongly associated with in-hospital mortality (38% versus 4%; P=0.005). Of the 109 stroke-free subjects with postoperative magnetic resonance imaging, silent infarct was identified in 59 (54%). Silent infarct was not associated with in-hospital mortality or increased length of stay. Conclusions— Clinical stroke after AVR was more common than reported previously, more than double for this same cohort in the Society for Thoracic Surgery database, and silent cerebral infarctions were detected in more than half of the patients undergoing AVR. Clinical stroke complicating AVR is associated with increased length of stay and mortality.Background— The incidence and impact of clinical stroke and silent radiographic cerebral infarction complicating open surgical aortic valve replacement (AVR) are poorly characterized. Methods and Results— We performed a prospective cohort study of subjects ≥65 years of age who were undergoing AVR for calcific aortic stenosis. Subjects were evaluated by neurologists preoperatively and postoperatively and underwent postoperative magnetic resonance imaging. Over a 4-year period, 196 subjects were enrolled at 2 sites (mean age, 75.8±6.2 years; 36% women; 6% nonwhite). Clinical strokes were detected in 17%, transient ischemic attack in 2%, and in-hospital mortality was 5%. The frequency of stroke in the Society for Thoracic Surgery database in this cohort was 7%. Most strokes were mild; the median National Institutes of Health Stroke Scale was 3 (interquartile range, 1–9). Clinical stroke was associated with increased length of stay (median, 12 versus 10 days; P =0.02). Moderate or severe stroke (National Institutes of Health Stroke Scale ≥10) occurred in 8 (4%) and was strongly associated with in-hospital mortality (38% versus 4%; P =0.005). Of the 109 stroke-free subjects with postoperative magnetic resonance imaging, silent infarct was identified in 59 (54%). Silent infarct was not associated with in-hospital mortality or increased length of stay. Conclusions— Clinical stroke after AVR was more common than reported previously, more than double for this same cohort in the Society for Thoracic Surgery database, and silent cerebral infarctions were detected in more than half of the patients undergoing AVR. Clinical stroke complicating AVR is associated with increased length of stay and mortality. # CLINICAL PERSPECTIVE {#article-title-47}

Summary of evidence-based guideline update: Prevention of stroke in nonvalvular atrial fibrillation Report of the Guideline Development Subcommittee of the American Academy of Neurology

Objective: To update the 1998 American Academy of Neurology practice parameter on stroke prevention in nonvalvular atrial fibrillation (NVAF). How often do various technologies identify previously undetected NVAF? Which therapies reduce ischemic stroke risk with the least risk of hemorrhage, including intracranial hemorrhage? The complete guideline on which this summary is based is available as an online data supplement to this article. Methods: Systematic literature review; modified Delphi process recommendation formulation. Major conclusions: In patients with recent cryptogenic stroke, cardiac rhythm monitoring probably detects occult NVAF. In patients with NVAF, dabigatran, rivaroxaban, and apixaban are probably at least as effective as warfarin in preventing stroke and have a lower risk of intracranial hemorrhage. Triflusal plus acenocoumarol is likely more effective than acenocoumarol alone in reducing stroke risk. Clopidogrel plus aspirin is probably less effective than warfarin in preventing stroke and has a lower risk of intracranial bleeding. Clopidogrel plus aspirin as compared with aspirin alone probably reduces stroke risk but increases the risk of major hemorrhage. Apixaban is likely more effective than aspirin for decreasing stroke risk and has a bleeding risk similar to that of aspirin. Major recommendations: Clinicians might obtain outpatient cardiac rhythm studies in patients with cryptogenic stroke to identify patients with occult NVAF (Level C) and should routinely offer anticoagulation to patients with NVAF and a history of TIA/stroke (Level B). Specific patient considerations will inform anticoagulant selection in patients with NVAF judged to need anticoagulation.

Vascular Risk Factors and Cognitive Impairment in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort (CRIC) Study

BACKGROUND AND OBJECTIVES Cognitive impairment is common among persons with chronic kidney disease, but the extent to which nontraditional vascular risk factors mediate this association is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted cross-sectional analyses of baseline data collected from adults with chronic kidney disease participating in the Chronic Renal Insufficiency Cohort study. Cognitive impairment was defined as a Modified Mini-Mental State Exam score>1 SD below the mean score. RESULTS Among 3591 participants, the mean age was 58.2±11.0 years, and the mean estimated GFR (eGFR) was 43.4±13.5 ml/min per 1.73 m2. Cognitive impairment was present in 13%. After adjustment for demographic characteristics, prevalent vascular disease (stroke, coronary artery disease, and peripheral arterial disease) and traditional vascular risk factors (diabetes, hypertension, smoking, and elevated cholesterol), an eGFR<30 ml/min per 1.73 m2 was associated with a 47% increased odds of cognitive impairment (odds ratio 1.47, 95% confidence interval 1.05, 2.05) relative to those with an eGFR 45 to 59 ml/min per 1.73 m2. This association was attenuated and no longer significant after adjustment for hemoglobin concentration. While other nontraditional vascular risk factors including C-reactive protein, homocysteine, serum albumin, and albuminuria were correlated with cognitive impairment in unadjusted analyses, they were not significantly associated with cognitive impairment after adjustment for eGFR and other confounders. CONCLUSIONS The prevalence of cognitive impairment was higher among those with lower eGFR, independent of traditional vascular risk factors. This association may be explained in part by anemia.

Practice advisory: Recurrent stroke with patent foramen ovale (update of practice parameter) Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

Objective: To update the 2004 American Academy of Neurology guideline for patients with stroke and patent foramen ovale (PFO) by addressing whether (1) percutaneous closure of PFO is superior to medical therapy alone and (2) anticoagulation is superior to antiplatelet therapy for the prevention of recurrent stroke. Methods: Systematic review of the literature and structured formulation of recommendations. Conclusions: Percutaneous PFO closure with the STARFlex device possibly does not provide a benefit in preventing stroke vs medical therapy alone (risk difference [RD] 0.13%, 95% confidence interval [CI] −2.2% to 2.0%). Percutaneous PFO closure with the AMPLATZER PFO Occluder possibly decreases the risk of recurrent stroke (RD −1.68%, 95% CI −3.18% to −0.19%), possibly increases the risk of new-onset atrial fibrillation (AF) (RD 1.64%, 95% CI 0.07%–3.2%), and is highly likely to be associated with a procedural complication risk of 3.4% (95% CI 2.3%–5%). There is insufficient evidence to determine the efficacy of anticoagulation compared with antiplatelet therapy in preventing recurrent stroke (RD 2%, 95% CI −21% to 25%). Recommendations: Clinicians should not routinely offer percutaneous PFO closure to patients with cryptogenic ischemic stroke outside of a research setting (Level R). In rare circumstances, such as recurrent strokes despite adequate medical therapy with no other mechanism identified, clinicians may offer the AMPLATZER PFO Occluder if it is available (Level C). In the absence of another indication for anticoagulation, clinicians may routinely offer antiplatelet medications instead of anticoagulation to patients with cryptogenic stroke and PFO (Level C).

Factors Associated With Intracerebral Hemorrhage After Thrombolytic Therapy for Ischemic Stroke Pooled Analysis of Placebo Data From the Stroke-Acute Ischemic NXY Treatment (SAINT) I and SAINT II Trials

Background and Purpose— A number of factors have been associated with postthrombolysis intracerebral hemorrhage, but these have varied across studies. Methods— We examined patients with acute ischemic stroke treated with intravenous tissue plasminogen activator within 3 hours of symptom onset who were enrolled in the placebo arms of 2 trials (Stroke-Acute Ischemic NXY Treatment [SAINT] I and II Trials) of a putative neuroprotectant. Early CT changes were graded using the Alberta Stroke Program Early CT Score (ASPECTS). Post–tissue plasminogen activator symptomatic intracerebral hemorrhage was defined as a worsening in National Institutes of Health Stroke Scale of ≥4 points within 36 hours with evidence of hemorrhage on follow-up neuroimaging. Good clinical outcome was defined as a modified Rankin scale of 0 to 2 at 90 days. Results— Symptomatic intracerebral hemorrhage occurred in 5.6% of 965 patients treated with tissue plasminogen activator. In multivariable analysis, symptomatic intracerebral hemorrhage was increased with baseline antiplatelet use (single antiplatelet: OR, 2.04, 95% CI, 1.07 to 3.87, P=0.03; double antiplatelet: OR, 9.29, 3.28 to 26.32, P<0.001), higher National Institutes of Health Stroke Scale score (OR, 1.09 per point, 1.03 to 1.15, P=0.002), and CT changes defined by ASPECTS (ASPECTS 8 to 9: OR, 2.26, 0.63 to 8.10, P=0.21; ASPECTS ≤7: OR, 5.63, 1.66 to 19.10, P=0.006). Higher National Institutes of Health Stroke Scale was associated with decreased odds of good clinical outcome (OR, 0.82 per point, 0.79 to 0.85, P<0.001). There was no relationship between baseline antiplatelet use or CT changes and clinical outcome. Conclusions— Along with higher National Institutes of Health Stroke Scale and extensive early CT changes, baseline antiplatelet use (particularly double antiplatelet therapy) was associated with an increased risk of post–tissue plasminogen activator symptomatic intracerebral hemorrhage. Of these factors, only National Institutes of Health Stroke Scale was associated with clinical outcome.

Percutaneous Device Closure of Patent Foramen Ovale for Secondary Stroke Prevention: A Call for Completion of Randomized Clinical Trials: A Science Advisory From the American Heart Association/American Stroke Association and the American College of Cardiology Foundation The American Academy of Neurology affirms the value of this science advisory.

The optimal therapy for prevention of recurrent stroke or transient ischemic attack in patients with cryptogenic stroke and patent foramen ovale has not been defined. Although numerous observational studies have suggested a strong association between patent foramen ovale and cryptogenic stroke, a causal relationship has not been convincingly established for the majority of affected patients. Treatment choices include medical therapy with antiplatelet agents or vitamin K antagonists, percutaneous device closure, or open surgical repair. Whereas suture closure of an incidental patent foramen ovale is performed routinely during the course of an operation undertaken for another indication, primary surgical repair is rarely advocated in the current era. The choice between medical therapy and percutaneous device closure has been the subject of intense debate over the past several years, albeit one that has not been adequately informed by randomized, prospective clinical trial data to permit an objective comparison of the relative safety and efficacy of these respective approaches. Enrollment in clinical trials has lagged considerably despite frequent calls for participation from the US Food and Drug Administration and major professional societies. Completion and peer review of ongoing trials are critical steps to establish an evidence base from which clinicians can make informed decisions regarding the best therapy for individual patients. The present advisory strongly encourages all clinicians involved in the care of appropriate patients with cryptogenic stroke and patent foramen ovale--cardiologists, neurologists, internists, radiologists, and surgeons--to consider referral for enrollment in these landmark trials to expedite their completion and help resolve the uncertainty regarding optimal care for this condition.